Food for Thought: Approaches to formulating products in the growing cognitive health space

Photo © Jolygon - Stock.adobe.com

Brain health is among the health concerns in which consumers can immediately recognize deficiencies. We can feel stress, lack of focus, lethargy, and the occasional lapse in memory. For the proactive consumer, dietary supplements offer a potential way to manage one’s cognitive health, and many are turning to them. According to market researcher SPINS (Chicago), in the 52 weeks ending October 31, 2021, sales of cognitive health ingredients in the mainstream supplements market grew 59%. This came on top of 69% sales growth the previous year.

There are many paths to cognitive support, and creating a product that’s just right for your target customer can be daunting. The good news is there is no shortage of innovative ingredients that can help you meet the overwhelming demand for brain health products.

The Long Haul

Proper nutrition, like with all our body’s organ systems, is key to proper cognitive function, particularly during our early development. This is why omega-3 DHA and EPA fatty acids are important for both pregnant women and infants, finding their way into prenatal dietary supplements and baby formulas. A meta-analysis¹ conducted by Cochrane in 2018, for example, found that supplementation with omega-3 supplements helped reduce preterm birth (<37 weeks of gestation) and very preterm birth (<34 weeks of gestation) by 11% and 47%, respectively.

Another study² published in the Journal of Nutritional Biochemistry found that children between two and six years of age with high omega-3 index levels were three to four times more likely to pass one or more dimensional change card sort tasks, compared to children with low omega-3 index levels. These tasks are used to measure executive function and require attention and flexibility from subjects. Of course, more research is necessary to truly understand how omega-3 levels in the body influence cognitive function in children as they grow up.

“We know that kids with ADHD have lower omega-3 levels, but it’s still not clear whether that’s a consequence of the quirky dietary patterns of these kids or if it’s contributing to the cause of ADHD,” says William S. Harris, PhD, FASN, president of the Fatty Acid Research Institute and founder of OmegaQuant Analytics. “Of course, there is considerable evidence that higher omega-3 levels in later years—and probably in midlife, if we had the data to look at—is a strong predicter of better cognitive health into the sunset years.”

How omega-3 levels at an early age set the stage for later cognitive performance or decline is a more difficult question to answer. “To address that question, you would need blood omega-3 levels in (ideally) children and then see who develops dementia by age 75,” says Harris. “Imagine how long that study would take to run! It’s reasonable from what we know today that keeping omega-3 levels high throughout life will have long-term health and mental benefits.”

Indeed, the goal to maintain healthy omega-3 levels should not end early in life. This category of ingredients has the potential to benefit all life stages. Pregnant women want their children to develop properly in the womb and therefore take omega-3 themselves. This supplementation then shifts to children. Ideally, supplementation continues into adulthood. The advantage of omega-3s is that they support multiple health concerns, including cardiovascular health and joint health. Cognitive health can be another motivating factor to encourage omega-3 supplementation.

Another way to motivate consumers to take ongoing, long-term action on cognitive support is through personalized nutrition and at-home testing which allows consumers to actively monitor their own health from home. OmegaQuant, for example, offers Omega-3 Index test kits, including prenatal DHA tests and Mother’s Milk DHA tests, as well as vitamin B12 tests. Poor levels of vitamin B12 have been associated with increased risk of dementia, and vitamin B12 is important for proper cardiovascular and nerve function.

Being able to track one’s progress is empowering and can be a valuable resource for dietary supplement brands. One brand, d.velop, offers vitamin D test kits alongside vitamin D supplements, allowing customers to get a before-and-after picture of their nutritional status. Strategies like this help reinforce the importance of staying dedicated to proper nutrition, even if physiologic benefits are not felt right away.

The growth potential for ingredients like omega-3s DHA and EPA is promising. Data from SPINS show that the sale of fish oil concentrates grew 106% in the cognitive health category of the mainstream multioutlet channel in 2021, compared to the previous year.

Another ingredient that may support cognitive health long term is the phospholipid phosphatidylserine. According to SPINS, in 2021 sales of phosphatidylserine ingredients grew 90% in the cognitive health category of the mainstream multioutlet channel, over the previous year.

Research has shown that phosphatidylserine plays an important role in the human brain. It is required for healthy nerve cell membranes and myelin, and has been associated with the formation of short-term memory, consolidation of long-term memory, the ability to retrieve memories, the ability to learn and recall information, the ability to focus attention and concentrate, the ability to reason and solve problems, language skills, as well as the ability to communicate.³

And, while long-term cognitive health remains important to consumers, more immediate concerns for energy, focus, and stress management may offer more tangible benefits in the short term, making products concentrated on these features incredibly attractive to consumers.

Think Fast

Gasoline may fuel our cars, but coffee fuels our bodies. We rely on coffee and other caffeinated beverages to dissipate that morning fog and get our day started. Unfortunately, caffeine has its limits and may produce diminishing returns throughout the day. Contending with the infamous “crash” is changing the way people think about energy. Just because you’re not falling asleep at your desk doesn’t mean you have energy. In fact, energy is increasingly being tied to focus.

“Your brain needs energy to focus. Low energy equals low focus. The problem with typical stimulants like caffeine is that they can cause jitteriness and ‘scatter brain,’” says Roy Krebs, founder and CEO of Natural Stacks, a dietary supplement brand focused largely on brain health formulas.

“I think we’ve all found that frenetic energy derived from consuming a lot of caffeine may help at times but is often distracting and fragmenting to a productive thought process,” offers Cal Bewicke, CEO of Ethical Naturals Inc. (Novato, CA), which manufactures AlphaWave L-theanine.

Dietary supplements offer a solution to either complement the energy we get from caffeinated beverages or provide an alternative approach to keeping our minds sharp. L-theanine is an excellent example of an ingredient that can complement our favorite caffeinated beverages and is making its way into mainstream products. For example, Mountain Dew launched a line of energy drinks marketed toward gamers that incorporates L-theanine, in addition to caffeine, ginseng extract, and yerba mate extract.

One study⁴ found that the combination of L-theanine with caffeine had a significant impact on subjects’ performance of a demanding visuospatial attention task compared to placebo, L-theanine alone, or caffeine alone. Researchers in this study also collected electrophysiological data by scanning alpha-band activity. These scans measured indices of tonic (background) and phasic (event-related) visuospatial attention deployment. Results showed that the combination of L-theanine and caffeine lowered overall tonic alpha power, meaning that the subjects were able to devote more attention to the task. Brainwave alpha power is believed to be indicative of relaxation.

An herbal ingredient that is seeing major sales growth in the cognitive health space is Bacopa monnieri. According to SPINS, in the 52 weeks ending October 31, 2021, sales of bacopa ingredients in the cognitive health category of the mainstream supplements market grew 117%, compared to the previous year. The ingredient’s long history of use, both in traditional Ayurvedic medicine and modern dietary supplements, may have something to do with its sales growth.

“[Our proprietary bacopa extract] Bacopin is one Sabinsa’s earliest products to support memory and concentration. It has often helped even professional chess players,” says Muhammed Majeed, PhD, founder and president of Sami-Sabinsa Group, the parent company of Sabinsa Corp. (East Windsor, NJ). “The active ingredients are the Bacopa saponins present in the extract. Generally, these Bacopa saponins have been shown to exert their memory-stabilizing activities through acetylcholinesterase inhibition, sustaining neurotransmitter acetylcholine and other neurotransmitters such as dopamine and serotonin. Also, nearly 20% of all the blood pumped by the heart flows through the brain, so optimal cerebral blood flow is quite important for brain health, and Bacopa extract helps in that process.”

In a study⁵ published in the Journal of Alternative and Complementary Medicine, 98 adults over the age of 55 years of age were given either 300 mg/day of bacopa or placebo for 12 weeks. Researchers measured audioverbal and visual memory performance with the Auditory Verbal Learning Test (AVLT), the Rey-Osterrieth Complex Figure Test (CFT), and the Reitan Trail Making Test (TMT). Results showed that subjects taking the bacopa extract experienced significant improvements in verbal learning, memory acquisition, and delayed recall based on AVTL, total learning, and retroactive interference.

The popularity of speed chess may have been overtaken by video games, but gamers are looking for that mental edge as well. Ingredient manufacturers are therefore actively marketing their products for the esports category, and many manufacturers have been wise to launch products to meet demand in this space.

“Gaming is on the rise throughout the globe. It is a legitimate form of endurance competition, luring players in a formal global competitive arena,” says Abey Thomas, head of global marketing, Natural Remedies (Bangalore, India), which manufactures a proprietary bacopa extract called BacoMind. “For example, the International Esports Federation (IESF) recently announced a total prize pool of $500,000 to be awarded at the upcoming 14^th WE Championships Finals, taking place in Bali, Indonesia, later this year (2022).”

Annie Eng, CEO of HP Ingredients (Bradenton, FL), agrees. “The vitality of the esports market is one that neatly encompasses dietary supplements for mental energy endurance and sustainability of cognitive acuity,” she states. “This is no longer just kids playing video games to compete after school. According to data from Newzoo, revenue for esports is expected to reach $1.8 billion this year.”

Of course, the benefits of cognitive health ingredients are not limited to esports but can absolutely be applied to numerous product categories that emphasize performance.

“Participants and competitors in more physical sports competition that involves intense, enduring focus (marathon events), acute short-term focus (gymnastics, weightlifting), and strategy (football) also will benefit from brain-support supplementation,” says Thomas.

And it’s not just athletes that care about results. “We see a fertile area of opportunity in young adults (in their 20s and 30s) who are rooting themselves in career and family life and dealing with stress and tension, which tend to erode concentration and cognitive acuity,” continues Thomas. “The concepts of ‘focus,’ ‘attention,’ and ‘cognitive endurance’ are very attractive to this wide demographic.”

Categories like esports that use mental acuity as a performance matrix are important for the sale of cognitive health ingredients because products that have been historically marketed for supporting memory have long been a difficult sell to younger consumers. These new markets open up cognitive health ingredients to a broader demographic of consumers and help manufacturers differentiate themselves in an overall category. For example, a cognitive health claim on a sports nutrition product may just be one of the deciding factors for purchase when you consider the highly saturated sports nutrition market.

Ingredients like Andrographis paniculata offer multi-pronged benefits such as joint health, muscle health, immunity, and cognitive function. This makes the ingredient highly versatile and ideal for inclusion in sports nutrition, cognitive health, and healthy-aging products.

According to Eng at HP Ingredients, which markets the extracts Paractin and Neuroactin, Andrographis paniculata may support cognitive health through a variety of mechanisms: 1) the inhibition of NF-kappaB, thus reducing inflammation in the brain; and 2) the activation of canonical and non-canonical Wnt signaling, which plays a vital role in the nervous system such as early patterning of the nervous system and higher functions such as synaptic plasticity and memory in adults. The ingredient has also been associated with the inhibition of glycogen synthase kinase-3 beta, which regulates mitochondrial-dependent apoptosis, and the reduction of tau hyperphosphorylation, says Eng.

Similarly, ashwagandha (Withania somnifera), a popular ingredient that offers a diverse set of benefits, is seeing greater consumer recognition each year. As an adaptogenic herb, it can support immunity, athletic performance, and stress, making it a desirable ingredient.

“Ashwagandha is a stress reliever and has an immune component to its mechanism of action. Ashwagandha is a well-known but often misunderstood or underrated ingredient,” says Majeed. “Ashwagandha mainly exerts its action through its actives known as withanolides. It is important that the product is standardized for withanolides and that the ingredient company explicitly states their content.”

Stress is important to address because it impacts our lives in many ways, cognitive wellness being one of them.

Calming Down

Stress can inhibit focus, says Bewicke. “Stress is a complex life occurrence essential for survival and goal achievement but can be damaging in excess,” he explains. “Whether it’s in sports, writing, art, or solving problems at work, high stress levels can interfere with the ability to concentrate and stay focused. To be really successful at any complex task, we need energy, but we also need to be ‘in the zone’ to access that mental space where our attention, focus, and intelligence can all come together.”

Recently, a study⁶ found that, compared to placebo, supplementation with AlphaWave L-theanine significantly increased frontal lobe alpha power three hours post-dose following a stress-inducing mental arithmetic test. Following the test, subjects taking L-theanine also saw significantly greater reductions in salivary cortisol one hour post-dose, compared to placebo. The decreased levels of salivary cortisol as early as an hour after dosage provides support for the subsequent increase in alpha power, suggesting that L-theanine may support acute stress.

Another ingredient that may help one function better under stressful conditions is Persicaria minor, also known as kesum in Malaysia and Singapore. A recent study⁷ published in BMC Complementary Medicine and Therapies found that older adults with mild cognitive impairment taking 250 mg of a proprietary extract of Persicaria minor from HP Ingredients, called IQ200, twice daily for six months experienced significant improvements in visual memory and negative mood such as tension, anger, and confusion. Negative emotions can be a symptom of stress as well as exacerbate it. While stress is temporary, it can become chronic, and if stressors pile on stressors, it can very negatively impact our health.

“Long-term stress can cause biological vulnerability,” says Eng. “A stressful event causes a cascade of events in the endocrine, immune, and cardiovascular systems. Stress is known to stimulate production of pro-inflammatory cytokines, which may impact mental health and cognitive performance.”

A relatively recent innovation in the cognitive health space is probiotic supplements. Over the years, consumers have embraced probiotics as a way to improve their gut health. During that time, the body of research elucidating how the gut microbiome affects other aspects of our health, including cognitive function, has also grown. Stress can have a negative impact on our gut microbiome and, in turn, our gut microbiome may affect how we manage stress.

“Resident microbes within our gut produce a multitude of neuroactive compounds that influence the way we think, feel, and perform,” explains Trevor Wagner, global health category manager at IFF Health (New York City). “These include neurotransmitters like gamma aminobutyric acid (GABA), noradrenaline, dopamine, and serotonin; amino acids like tyramine and tryptophan; and microbial metabolites such as short-chain fatty acids.”

He continues: “These metabolites can travel through portal circulation to interact with our immune system, and they can influence metabolism or even affect local neuronal cells of the enteric nervous system (a network of nerves located within the gastrointestinal tract). In fact, the enteric nervous system is so important it is often referred to as our second brain—and from here, metabolites signal along afferent pathways of the vagus nerve that carries information from the gut directly to the brain.”

Within the nervous system, stress activates the hypothalamic pituitary adrenal axis. This triggers a cascade of hormone production that ultimately results in the production and release of cortisol from the adrenal glands into portal circulation, says Wagner.

“These stress hormones, along with immune-mediators and various neurotransmitters, can change the gut environment and alter the microbiota composition over time,” he explains. “This can have detrimental effects on both physical and mental health. Within the gut, cortisol can affect intestinal barrier integrity and immune signaling, and stress itself has been associated with changes in the composition of the gut microbiota. In other words, ongoing stress can take its toll on the body by harming beneficial bacteria.”

As a result, manufacturers have developed probiotic strains that address cognitive health outcomes such as mood. IFF, for example, markets Howaru Lacticaseibacillus paracasei Lpc-37 to support stress. While the exact mechanisms of its action are not fully understood, the ingredient has shown positive outcomes in humans. In one study⁸, 120 healthy adults were given either the probiotic or placebo for five weeks. Results showed that supplementation with the probiotic significantly reduced perceived exhaustion and fatigue as well as perceived stress. The reduction in perceived stress was particularly pronounced among female subjects. (Interestingly, the researchers noted that women in the study had higher stress and sleep disruption and felt less rested after a night’s sleep compared to men in the study, indicating that sex may be an underlying factor that influences the stress response.)

There is the potential to combine probiotic ingredients such as this with other cognitive-supporting ingredients. For example, IFF found success in combining its Lpc-37 probiotic with a soy phosphatidylserine called Sharp PS. “After testing formulas under different storage conditions and delivery formats, we successfully confirmed the perceived stress-reducing probiotic strain Lpc-37 can be combined with memory-boosting Sharp-PS,” says Wagner. “For 18 months, we ran a stability study with both ingredients and are happy to report a lack of effect on probiotic stability.”

That said, not all combinations are possible due to issues of stability. “Brand owners should keep in mind that just because two ingredients’ mechanisms of action complement each other, it doesn’t mean they make a good combination,” explains Wagner. “Probiotics are sensitive to heat, water, pH, and potentially even oxygen, so dietary supplements must be carefully crafted to ensure stability at each stage of development.”

The Finished Product

While consumers are looking for solutions to support their mental health, they also want to be careful about what they put into their bodies. Clinically supported ingredients help lend credibility to a product, and transparency about one’s ingredients earns you the trust of consumers. In a category where demand is high, there will be many unscrupulous manufacturers making subpar products that capitalize on a trend. It’s important to stand out with quality ingredients and transparency. For example, Natural Stacks has a transparency program that provides consumers with ingredient traceability, third-party testing, and full label disclosure.

“The Natural Stacks Open Source transparency program informs the consumer exactly what they’re putting into their body. It builds trust,” Krebs states. “By scanning a QR code on the bottle, you can see where every single ingredient came from and the third-party lab test verifying the purity and potency. The supplement market is fairly unregulated. We feel like it’s our duty to go above and beyond what’s required.”

“Besides seeking suppliers with thorough quality-control procedures, we also do third-party identity testing when qualifying ingredients,” he continues. “This is especially important with herbal extracts because there’s a lot of adulteration in the market. Once we vet ingredient suppliers, we use them batch after batch. Regardless of price fluctuations, we don’t ‘shop’ ingredients for each production run like some large producers might do. This way, we can ensure consistency and quality.”

Consumers also love convenience, making innovative dosage formats attractive. One brand, called FourSigmatic, successfully combined the world’s favorite beverage, coffee, with functional mushrooms to support cognitive health and mood. For example, FourSigmatic’s Think line of coffee products combines coffee with Lion’s mane mushrooms and chaga mushrooms.

“Lion’s mane supports focus, memory, and concentration as well as the nervous and immune systems. We like to say that our Think Ground Coffee is like a hug for your brain since it has cognitive-enhancing properties that can help improve focus without the jittery effects that so often accompany regular coffee,” says Danielle Ryan Broida, RH, AHG, national educator at FourSigmatic. “Chaga, known as the ‘King of Mushrooms,’ is a powerful immune-supporting species full of antioxidant properties which has been an important part of Nordic folk medicine for hundreds of years.”

The key to making functional food and beverage items that consumers know well and are fond of is, unsurprisingly, great taste. The hurdle here is getting consumers to switch from their favorite coffee brands.

“When coming to the states from Finland, our founders had a big idea of getting Americans to drink mushrooms, but mushrooms weren’t exactly an embraced concept,” says Broida. “Our success came from winning in taste and benefit. Once people tried our coffee, they realized that it tasted like coffee, not like mushrooms at all. And when they felt the benefits like increased energy, focus, and reduced stress, it was an easy swap.”

Innovative dosage formats offer convenience and novelty, but traditional dosage formats, for the most part, offer consistency and reliability. As Krebs explains, if a product works, people will take it. Natural Stacks sells multiproduct “stacks” to support specific aspects of cognitive health, most of which are traditional capsules.

“People are willing to do what it takes to get the best results. With traditional vegetable capsules, we can utilize fully effective doses of each ingredient and formulate to yield maximum benefit,” says Krebs. “However, we are also working on alternative delivery methods for the demographic of people who prefer not to take multiple capsules. Mood and stress are the most widespread health problems of our time. It’s our mission to build better brains so we will continue to innovate to reach and help more households.”

The innovation never ends; the challenge is keeping up. Ultimately, consumers want quality products that give them results.

References

1. Middleton P et al. “Omega-3 fatty acid addition during pregnancy.” Cochrane Database of Systematic Reviews, vol. 11, no. 11 (November 15, 2018)
2. Adjepong M et al. “Whole blood n-3 fatty acids are associated with executive function in 2–6-year-old Northern Ghanaian children.” Journal of Nutritional Biochemistry, vol. 57 (July 2018): 287-293
3. Glade MJ et al. “Phosphatidylserine and the human brain.” Nutrition, vol. 31, no. 6 (June 2015): 781-786
4. Kelly SP et al. “L-theanine and caffeine in combination affect human cognition as evidenced by oscillatory alpha-band activity and attention task performance.” The Journal of Nutrition, vol. 138, no. 8 (August 2008): 1572S-1577S
5. Morgan A et al. “Does Bacopa monnieri improve memory performance in older persons? Results of a randomized, placebo-controlled, double-blind trial.” Journal of Alternative and Complementary Medicine, vol. 16, no. 7 (July 2010): 753-759
6. Evans M et al. “A randomized, triple-blind, placebo-controlled, crossover study to investigate the efficacy of a single dose of AlphaWave L-theanine on stress in a healthy adult population.” Neurology and Therapy, vol. 10, no. 2 (December 2021): 1061-1078
7. Lau H et al. “The effects of six months Persicaria minor extract supplement among older adults with mild cognitive impairment: A double-blinded, randomized, and placebo-controlled trial.” BMC Complementary Medicine and Therapies, vol. 20, no. 1 (October 19, 2020): 315
8. Patterson Elaine et al. “Lacticaseibacillus paracasei Lpc-37® improves psychological and physiological markers of stress and anxiety in healthy adults: A randomized, double-blind, placebo-controlled and parallel clinical trial (the Sisu study).” Neurobiology of Stress. Published online November 24, 2020.